Antiphospholipid SyndromeAntiphospholipid Syndrome

Prof. Dr. Suchitra N. PanditProf. Dr. Suchitra N. PanditMD, DNBE, DFP, FRCOG, FICOG, B.Pharm

Consultant Obstetrician & Gynaecologist

Kokilaben Dhirubhai Hospital, Mumbai ,IndiaClinical secretary –MOGS, Vice President - FOGSI (2008-09)

Chairperson -Young Talent promotion committee FOGSI (2003-07)

Antiphospholipid syndrome (Hughes syndrome) is aAntiphospholipid syndrome (Hughes syndrome) is a

disorder of immune system ,characterised by excessive disorder of immune system ,characterised by excessive clotting of blood ,thrombocytopenia & /or adverse clotting of blood ,thrombocytopenia & /or adverse pregnancy outcomespregnancy outcomes

Body recognizes negatively charged phospholipids on Body recognizes negatively charged phospholipids on cell membrane as foreign & produces antibodies cell membrane as foreign & produces antibodies against them leading to an acquired autoimmune against them leading to an acquired autoimmune thrombophiliathrombophilia

Patients have laboratory evidence for antibodies ( IgG, Patients have laboratory evidence for antibodies ( IgG, IgM or IgA ) against phospholipids or phospholipid-IgM or IgA ) against phospholipids or phospholipid-binding protein cofactors in their bloodbinding protein cofactors in their blood

Antiphospholipid ( Antiphospholipid ( APLAAPLA ) syndrome ) syndrome

How many types of APLA syndromes are thereHow many types of APLA syndromes are there

A.) OneA.) One

B.) two B.) two

C.) ThreeC.) Three

D.) FourD.) Four

Antiphospholipid antibody syndrome (APLA)Antiphospholipid antibody syndrome (APLA)

Primary antiphospholipid syndromePrimary antiphospholipid syndrome (PAPS) - when APS (PAPS) - when APS occurs in the absence of any other related disease (LA, ACL occurs in the absence of any other related disease (LA, ACL antibodies in patient’s serum).antibodies in patient’s serum).

Secondary antiphospholipid syndromeSecondary antiphospholipid syndrome - when APS coexists - when APS coexists with other diseases such as SLE Iwith other diseases such as SLE I

In catastrophic APLA (rare ), APS leads to rapid organ failure In catastrophic APLA (rare ), APS leads to rapid organ failure due to generalised thrombosis & a high risk of deathdue to generalised thrombosis & a high risk of death

Other rare antibodies to phosphotidyl ethanolamine & Other rare antibodies to phosphotidyl ethanolamine & phosphotidylserine are also associated with itphosphotidylserine are also associated with it

Thrombophilic defectseither acquired or inherited

Acquired

APLA Anticardiolipin antibodies

Lupus anticoagulant

antibodies

Thrombophilia - tendency to thrombosis

Myeloprolipherative diseases Malignancy Paroxysmal nocturnal Haemoglobinuria Nephrotic syndrome

Hyperhomocysteinemia (C677T) mutation Hyperhomocysteinemia (C677T) mutation

Factor V Leiden mutation (A506G) mutation Factor V Leiden mutation (A506G) mutation

Mutation in prothrombin ( G 20210 A) Mutation in prothrombin ( G 20210 A)

Prothrombin II (PTII) mutationProthrombin II (PTII) mutation

Protein S deficiencyProtein S deficiency

Protein C deficiencyProtein C deficiency

Inherited

All these conditions should be investigated for APLA All these conditions should be investigated for APLA except :except :

A.) Early onset severe preeclampsia A.) Early onset severe preeclampsia

B.) Arterial or venous thrombosis B.) Arterial or venous thrombosis

C.) Unexplained fetal growth restrictionC.) Unexplained fetal growth restriction

D.) Gestational Diabetes D.) Gestational Diabetes

Primary antiphospholipid antibody syndromePrimary antiphospholipid antibody syndrome

Presentation may be totally asymptomatic or in a classical manner :Presentation may be totally asymptomatic or in a classical manner : Various clinical presentations :Various clinical presentations : Recurrent pregnancy loss Recurrent pregnancy loss Unexplained second or third trimester loss Unexplained second or third trimester loss Early onset severe preeclampsia Early onset severe preeclampsia Arterial or venous thrombosis Arterial or venous thrombosis Unexplained fetal growth restrictionUnexplained fetal growth restriction Prolonged coagulation studies Prolonged coagulation studies Autoimmune diseases Autoimmune diseases Cardiac valvular diseases Cardiac valvular diseases Neurological disorders Neurological disorders ThrombocytopeniaThrombocytopenia

Diagnosis of APLADiagnosis of APLA

Challenging Challenging !!!!!!

Due to fluctuating titers of the antibodies, Due to fluctuating titers of the antibodies,

Lack of agreement between laboratories concerning Lack of agreement between laboratories concerning standardization of the assaysstandardization of the assays

Debates among researchers & clinicians concerning Debates among researchers & clinicians concerning which antibodies to measure.which antibodies to measure.

Which is not an APLA antibody ?Which is not an APLA antibody ?

A.) Anti RoA.) Anti Ro

B.) Lupus Anticoagulant (LAC)B.) Lupus Anticoagulant (LAC)

C.) Anticardiolipin Antibodies (ACL)C.) Anticardiolipin Antibodies (ACL)

D.) Anti insulin antibodiesD.) Anti insulin antibodies

Which are the AntibodiesWhich are the Antibodies

Lupus Anticoagulant (LAC)Lupus Anticoagulant (LAC)

Anticardiolipin Antibodies (ACL)Anticardiolipin Antibodies (ACL)

Anti Beta 2 glycoprotein antibodiesAnti Beta 2 glycoprotein antibodies

Other antibodiesOther antibodies

http://circ.ahajournals.org/content/vol112/issue3/images/large/23FF1.jpeg

Lupus anticoagulant ( LAC)Lupus anticoagulant ( LAC) LAC is characterized by a prolonged partial thromboplastin LAC is characterized by a prolonged partial thromboplastin

time & paradoxically the so-called ‘anticoagulant’ is a powerful time & paradoxically the so-called ‘anticoagulant’ is a powerful thrombotic agent in vivo thrombotic agent in vivo

Higher thrombotic potential than ACL when present alone Higher thrombotic potential than ACL when present alone

LAC interferes with platelet function, causing aggregation & LAC interferes with platelet function, causing aggregation & thrombosis & also interferes with endothelial function, causing thrombosis & also interferes with endothelial function, causing procoagulant activation & thrombosis procoagulant activation & thrombosis

Prevalence of LAC in low risk population is < 1% Prevalence of LAC in low risk population is < 1% Bad obstetric history - 9.1% Bad obstetric history - 9.1% Early pre eclampsia - 16%, Early pre eclampsia - 16%, Abruption - 33% Abruption - 33% Systemic lupus erythematosus - 34% Systemic lupus erythematosus - 34%

Patient typically has a prolonged APTT that does not Patient typically has a prolonged APTT that does not correct in 80:20 mixture with normal human plasmacorrect in 80:20 mixture with normal human plasma

Prolonged Dilute Russel viper venom time (DRVVT), Prolonged Dilute Russel viper venom time (DRVVT), Kaolin clotting test (KCT),(TDT/DTT) or prothombin timeKaolin clotting test (KCT),(TDT/DTT) or prothombin time

Due to heterogeneous nature of LA ,minimum of 2 tests Due to heterogeneous nature of LA ,minimum of 2 tests required, 6 weeks apart & should be positive each time required, 6 weeks apart & should be positive each time showing persistent positivity to confirm diagnosis of showing persistent positivity to confirm diagnosis of APLAAPLA Caution : patients with transient positive tests Caution : patients with transient positive tests (due to infection etc) can be diagnosed as positive.(due to infection etc) can be diagnosed as positive.

Lupus anticoagulant (LAC)Lupus anticoagulant (LAC) Prolongation of which of these tests is most Prolongation of which of these tests is most

sensitive for LAC ?sensitive for LAC ?

A.) Activated partial thromboplastin A.) Activated partial thromboplastin

B.) Dilute Russel Viper venom B.) Dilute Russel Viper venom

C.) Kaolin clotting timeC.) Kaolin clotting time

D.) Partial Thrombin timeD.) Partial Thrombin time

Anticardiolipin AntibodiesAnticardiolipin Antibodies Were thought to react against cardiolipin but it is Were thought to react against cardiolipin but it is

now thought to interact with B2GP1now thought to interact with B2GP1 85% of APS pts have both LA & aCL85% of APS pts have both LA & aCL

These can be detected using an (ELISA) These can be detected using an (ELISA)

Screens for the presence of β2 glycoprotein 1 Screens for the presence of β2 glycoprotein 1

dependent anticardiolipin antibodies (ACA)dependent anticardiolipin antibodies (ACA)

A low platelet count & positivity for antibodies A low platelet count & positivity for antibodies

against β2-glycoprotein 1 or phosphatidylserine against β2-glycoprotein 1 or phosphatidylserine

may also be observed in a positive diagnosismay also be observed in a positive diagnosis

Anti Beta 2 GP1Anti Beta 2 GP1 Discovered after LA & ACLDiscovered after LA & ACL

Found without other two in 11% of APS pts & Found without other two in 11% of APS pts &

commonly with others.commonly with others.

Binds to B2GP1 disrupting f(x)Binds to B2GP1 disrupting f(x)

B2GP1 has anticoagulant activity through the B2GP1 has anticoagulant activity through the

inhibition of the conversion of prothrombin-thrombin, inhibition of the conversion of prothrombin-thrombin,

regulation of protein S, & /or activation of platelets. regulation of protein S, & /or activation of platelets.

Sapporo criteriaSapporo criteria International Consensus Conference held in Sapporo International Consensus Conference held in Sapporo

(’98) (’98)

Clinical criteria of ( APAS )Clinical criteria of ( APAS )

Thrombosis, one or more confirmed episodes Thrombosis, one or more confirmed episodes

of venous, arterial, or small vessels diseaseof venous, arterial, or small vessels disease

‘ ‘ Coexisting inherited or acquired thromboticCoexisting inherited or acquired thrombotic

risk factors are not reasons for excluding risk factors are not reasons for excluding

patients from a diagnosis of APS trials.’patients from a diagnosis of APS trials.’

Sapporo Criteria (updated)Sapporo Criteria (updated)Pregnancy criteria :Pregnancy criteria :

One or more unexplained fetal deaths > 10 wks of pregnancy One or more unexplained fetal deaths > 10 wks of pregnancy One or more preeclampsia / eclampsia or placental One or more preeclampsia / eclampsia or placental

insufficiencies occurring before 34 weeks .insufficiencies occurring before 34 weeks . Three or more unexplained consecutive spontaneous Three or more unexplained consecutive spontaneous

abortions < 10 weeksabortions < 10 weeks

Laboratory criteriaLaboratory criteria LAC defined by a functional, clot-based assay (ISTH LAC defined by a functional, clot-based assay (ISTH

guidelines)guidelines) ACL (IgG or IgM) antibodyACL (IgG or IgM) antibody Anti-bAnti-b2 2 glycoprotein I ,IgG or IgM antibodyglycoprotein I ,IgG or IgM antibody

Miyakis, et al., J. Thromb. Haemost.,2006; 4: 295-306.

The International Consensus StatementThe International Consensus Statement

Definite CAPS diagnosis requires:Definite CAPS diagnosis requires:

Vascular thrombosis in three or more organs or tissues & Vascular thrombosis in three or more organs or tissues & development of manifestations simultaneously or in < a week & development of manifestations simultaneously or in < a week & small vessel thrombosis in at least one organ or tissue small vessel thrombosis in at least one organ or tissue

Lab. confirmation of presence of aPL Lab. confirmation of presence of aPL

Some serological tests for syphilis may be positive in aPL- positive Some serological tests for syphilis may be positive in aPL- positive patients if it is positive) although more specific tests for syphilis patients if it is positive) although more specific tests for syphilis that use recombinant antigens are negativethat use recombinant antigens are negative

Transient elevations common. Elevations common in autoimmune Transient elevations common. Elevations common in autoimmune disease & infections ex. HIV, Hep C, syphilisdisease & infections ex. HIV, Hep C, syphilis

Principal pathogenic mechanisms mediated by APL

Reduction of proliferation & differentiation; Gonadotrophin secretion impairment

a.) Trophoblast cells:

Interference with :

Induction of a pro-adhesive, pro-inflammatory & pro-coagulant endothelial  phenotype ;induction of a procoagulant phenotype in

monocytes

b.) Coagulation cells:

  Protein C/S pathway  inhibition;

  fibrinolysis inhibition

a.) Soluble coagulation factors

Interference with

Pregnancy losses classified as :Pregnancy losses classified as :

Occult (preclinical or chemical) pregnancy loss Occult (preclinical or chemical) pregnancy loss prior to missed menses. (40% of implantation prior to missed menses. (40% of implantation embryos)embryos)

Early pregnancy loss before 12 wk. (13%)Early pregnancy loss before 12 wk. (13%)

Late pregnancy loss after 12 wk. (1%)Late pregnancy loss after 12 wk. (1%)

Causes of pregnancy lossCauses of pregnancy loss

Chromosomal

55% of occult & early losses

5% of recurrent losses.

Environmental

hormonal

anatomical

Immunological

45% of early losses

95% of late losses

Standard of care is to offer genetic amniocentesis Standard of care is to offer genetic amniocentesis

for all pregnant women older than 35 yearsfor all pregnant women older than 35 years

Aneuploidy

Aneuploid fetus risk in women> 35yr. age

Inherent risk of fetal loss afteramniocentesis

1/80

1/200

What is Recurrent pregnancy loss ?

What actually causes it ?

DefinitionDefinition

A recurrent pregnancy loss (RPL) is 3 or more A recurrent pregnancy loss (RPL) is 3 or more consecutive, spontaneous pregnancy losses, under consecutive, spontaneous pregnancy losses, under 20 week gestation from the last menstrual period 20 week gestation from the last menstrual period by the same partner. by the same partner.

Primary recurrent pregnancy loss" refers to couples Primary recurrent pregnancy loss" refers to couples that have never had a live birth that have never had a live birth

““Secondary RPL" refers to those who have had Secondary RPL" refers to those who have had repetitive losses following a successful pregnancyrepetitive losses following a successful pregnancy

Pregnancy loss in the APLA syndrome - A Pregnancy loss in the APLA syndrome - A possible thrombogenic mechanism possible thrombogenic mechanism

Levels of annexin V, a phospholipid-binding protein with Levels of annexin V, a phospholipid-binding protein with potent anticoagulant activity, are markedly reduced on potent anticoagulant activity, are markedly reduced on placental villi from women with APLA placental villi from women with APLA

APL antibodies reduce the levels of annexin V & accelerate APL antibodies reduce the levels of annexin V & accelerate the coagulation of plasma on cultured trophoblasts & the coagulation of plasma on cultured trophoblasts & endothelial cells. endothelial cells.

Reduced annexin V levels on vascular cells may be an Reduced annexin V levels on vascular cells may be an important mechanism of thrombosis & pregnancy loss in important mechanism of thrombosis & pregnancy loss in APLA syndrome.APLA syndrome.

Jacob Rand, Xiao-Xuan Wu, H. Andree, CJ. Lockwood, Seth Guller, J Scher, Peter Harpel, -N Jacob Rand, Xiao-Xuan Wu, H. Andree, CJ. Lockwood, Seth Guller, J Scher, Peter Harpel, -N Engl J Med ; 337:1630-1631, 1997 Engl J Med ; 337:1630-1631, 1997

Pregnancy loss in autoimmune connective tissue Pregnancy loss in autoimmune connective tissue disorders (CTDs)disorders (CTDs)

Adverse outcomes like IUGR, prematurity, recurrent pregnancy Adverse outcomes like IUGR, prematurity, recurrent pregnancy loss & stillbirth are commonloss & stillbirth are common

Systemic lupus erythematosus (SLE) is prototype , others are Systemic lupus erythematosus (SLE) is prototype , others are rheumatoid arthritis, scleroderma, Behcet’s disease & Sjogren’s rheumatoid arthritis, scleroderma, Behcet’s disease & Sjogren’s syndromesyndrome

Recent studies show anti-Ro/SSA antibody as a possible factor Recent studies show anti-Ro/SSA antibody as a possible factor for unexplained pregnancy loss in SLE. for unexplained pregnancy loss in SLE.

Antibody is directed against cellular ribonucleoprotein Antibody is directed against cellular ribonucleoprotein complexes which is present in serum of > 10% pts of CTDs. complexes which is present in serum of > 10% pts of CTDs.

It is associated with neonatal lupus & congenital heart block It is associated with neonatal lupus & congenital heart block showing passively acquired autoimmunityshowing passively acquired autoimmunity

How do you proceed ?How do you proceed ? Interview the couple togetherInterview the couple together History of the case is very importantHistory of the case is very important Clinical examinationClinical examination Investigations as per the history Investigations as per the history Reassurance & counsellingReassurance & counselling Treatment plan : Drugs, maternal & fetal surveillance , Treatment plan : Drugs, maternal & fetal surveillance ,

dealing with complicationsdealing with complications Timely referral to a tertiary centreTimely referral to a tertiary centre

Special Investigations Special Investigations LAC tested by prolonged coagulation time (inhibition of LAC tested by prolonged coagulation time (inhibition of

phospholipids)phospholipids) APTT , KCT , TTITAPTT , KCT , TTIT Most accurate - Dilute russel viper venom test (DRVVT)Most accurate - Dilute russel viper venom test (DRVVT) ACL - ELISA - IgG (GPL) IgM (MPL)ACL - ELISA - IgG (GPL) IgM (MPL) IgG/ IgM isotypes of anticardiolipin & antiphosphotidyl IgG/ IgM isotypes of anticardiolipin & antiphosphotidyl

serine antibodiesserine antibodies In c/o low titres-repeat after 6-8wks (can revert to normal)In c/o low titres-repeat after 6-8wks (can revert to normal) Transient low titres can be found in viral feverTransient low titres can be found in viral fever If autoimmune disorders are suspected ANA, anti –nDNA, If autoimmune disorders are suspected ANA, anti –nDNA,

antiSm, anti-Ro/SSA antibody, anti La (SSP)antiSm, anti-Ro/SSA antibody, anti La (SSP)

General guidelines for anticoagulation in

Pregnancy with APS leading to recurrent

pregnancy loss

So how does one manage the drug

treatment in pregnancy ?

Very controversial issue !

Commonly used DrugsCommonly used Drugs• Steroids :Steroids : Reduces ACA, normalises prolongation of Reduces ACA, normalises prolongation of

invitro coagulation invitro coagulation • Complications :Complications : ? perinatal outcome ? perinatal outcome

preterm labour, preterm labour,

preeclampsiapreeclampsia• Low dose Aspirin (LDA) : Low dose Aspirin (LDA) : Selective inhibition of Selective inhibition of

Thromboxane A2Thromboxane A2

No effect on PGINo effect on PGI22

• Azathioprine Azathioprine • WarfarinWarfarin

Which is the commonly used drug for APLA ?Which is the commonly used drug for APLA ?

A.) ProgesteroneA.) Progesterone

B.) Folic acidB.) Folic acid

C.) Low dose AspirinC.) Low dose Aspirin

D.) RU- 486D.) RU- 486

Unfractionated Heparin (UFH)Unfractionated Heparin (UFH)

Potentiates complex formation with Potentiates complex formation with AT III + factor VII A AT III + factor VII A XII A & thrombin XII A & thrombin

Complications : Reduces platelet bleeding & Complications : Reduces platelet bleeding &

B.M.DB.M.D..

Low molecular weight Heparin (LMWH)Low molecular weight Heparin (LMWH) Once daily dose, less monitoring Once daily dose, less monitoring Lesser osteopenia, does not cross placentaLesser osteopenia, does not cross placenta Cost factor !!Cost factor !!

TrialsTrials Heparin vs Aspirin + prednisolone Heparin vs Aspirin + prednisolone

Live birth 75%Live birth 75%

Pre-eclampsia, preterm delivery more in latter Pre-eclampsia, preterm delivery more in latter group group

L.S. + LDA Vs Heparin + LDA (n=20)L.S. + LDA Vs Heparin + LDA (n=20) No placebo No placebo Large multicentric trials needed Large multicentric trials needed

Cowchock et al .1994Cowchock et al .1994

Randomised controlled trial of LDA versus LDA Randomised controlled trial of LDA versus LDA plus heparin in pregnant women with APSplus heparin in pregnant women with APS

90 women with APS were randomized into two groups with 190 women with APS were randomized into two groups with 1stst group receiving 75mg of LDA & 2nd group LDA & Heparin group receiving 75mg of LDA & 2nd group LDA & Heparin 5000u subcut, every 12 hourly5000u subcut, every 12 hourly

Outcomes measured were number of live births & miscarriagesOutcomes measured were number of live births & miscarriages

LDA group had 19 live births & 26 miscarriagesLDA group had 19 live births & 26 miscarriages

LDA + heparin group had 32 live births & 13 miscarriagesLDA + heparin group had 32 live births & 13 miscarriages

Significant (p=0.01) improvement in outcomes with heparin Significant (p=0.01) improvement in outcomes with heparin

R. Rai, R. Rai, H.Cohen et al..,BMJ. (1997 )H.Cohen et al..,BMJ. (1997 )

Antiphospolipid antibodiesAntiphospolipid antibodies

Presence of Antiphosholipid antibodies may cause Presence of Antiphosholipid antibodies may cause recurrent pregnancy lossrecurrent pregnancy loss

Are antibodies directly responsible ?Are antibodies directly responsible ?

Should all women with APA be treated ?Should all women with APA be treated ?

How do you treat a women with positive APLA ?How do you treat a women with positive APLA ?

Controversies surrounding treatment for pregnancy loss

Evidence-based medicine Evidence-based medicine

(EBM) has not succeeded in (EBM) has not succeeded in

giving patients & physicians giving patients & physicians

the data they need to choose the data they need to choose

(or not choose) a therapy in (or not choose) a therapy in

the field of pregnancy loss the field of pregnancy loss

Women with APLA are advised to take LDA & to start Women with APLA are advised to take LDA & to start LMWH Rx after pregnancy is diagnosed (80% success)LMWH Rx after pregnancy is diagnosed (80% success)

In case of H/o thrombotic symptoms, Warfarin is used In case of H/o thrombotic symptoms, Warfarin is used as anticoagulant .Maintain INR between 3.0 - 4.0. as anticoagulant .Maintain INR between 3.0 - 4.0.

Patients with APLA have minor elevations of PT & are Patients with APLA have minor elevations of PT & are difficult to manage with warfarin. difficult to manage with warfarin.

During pregnancy, LMWH & LDA are preferred to During pregnancy, LMWH & LDA are preferred to Warfarin (teratogenic effects )Warfarin (teratogenic effects )

If previous H/o thrombosis use LMWH in therapeutic If previous H/o thrombosis use LMWH in therapeutic doses throughout pregnancy :dose 1mg/kg subcut. doses throughout pregnancy :dose 1mg/kg subcut.

If UFH is used dose is 10,000 u 12 hourlyIf UFH is used dose is 10,000 u 12 hourly

Since APLA reacts with phospholipids both aPTT & PT can be Since APLA reacts with phospholipids both aPTT & PT can be affected. If UFH used to anticoagulate patients with APLA affected. If UFH used to anticoagulate patients with APLA monitor heparin levels ( 0.35 - 0.70 anti-Xa units 6 hours post monitor heparin levels ( 0.35 - 0.70 anti-Xa units 6 hours post injectiont ). injectiont ).

With LMWH , monitoring is easier : predictable dosing & With LMWH , monitoring is easier : predictable dosing & anticoagulant effect . Measure LMW heparin levels in these anticoagulant effect . Measure LMW heparin levels in these patients for long term Rx (0.7 - 1.0 anti-Xa units) patients for long term Rx (0.7 - 1.0 anti-Xa units)

Perform prothrombin & proconvertin times ("P&P") to follow Perform prothrombin & proconvertin times ("P&P") to follow anticoagulation. Being less dependent on phospholipids & one anticoagulation. Being less dependent on phospholipids & one can monitor therapy.can monitor therapy.

If miscarriage occurs with heparin & aspirin & there is a If miscarriage occurs with heparin & aspirin & there is a pregnancy again IVIG can be tried (RCT did not show benefit)pregnancy again IVIG can be tried (RCT did not show benefit)

In refractory cases plasmapheresis may be usedIn refractory cases plasmapheresis may be used

ACCP Guidelines : Pregnancy & APLACCP Guidelines : Pregnancy & APL

Manifestation Recommendation Grade

Antiphospholipid antibody; no prior VTE or pregnancy loss

Surveillance, or mini-dose heparin, or prophylactic LMWH, & /or aspirin

2C

Antiphospholipid antibody; prior thrombotic event

Adjusted dose UFH or LMWH, plus low-dose aspirin.

1C

- Bates, et al., Chest, 2004; 126: 627S - 644S

Can pregnancy outcome be improved ?Can pregnancy outcome be improved ?

Management of pregnant womenManagement of pregnant women Surveillance depends on past obstetric historySurveillance depends on past obstetric history

LDA preconception & LDA + LMWH has 80% success LDA preconception & LDA + LMWH has 80% success rate for treatment of APLA ( Feinberg et al,’ 97 ). rate for treatment of APLA ( Feinberg et al,’ 97 ).

Refer preferably to a tertiary centre with a neonatal backupRefer preferably to a tertiary centre with a neonatal backup

Team effort including an obstetrician , hematologist, Team effort including an obstetrician , hematologist, physician, & neonatologist physician, & neonatologist

Vigilant monitoringVigilant monitoring

B.P, platelets, complement levels , renal function test (to B.P, platelets, complement levels , renal function test (to asses target organ damage )asses target organ damage )

Care of the fetus Care of the fetus Surveillance depends on past obstetric history Surveillance depends on past obstetric history

11stst trim U.S.G : viability & dating , nuchal & nasal bone trim U.S.G : viability & dating , nuchal & nasal bone

U.S.G at 19 weeks & serial scans with doppler for early U.S.G at 19 weeks & serial scans with doppler for early diagnosis of IUGR & waveform abnormalitesdiagnosis of IUGR & waveform abnormalites

Inj Betamethasone 2 doses for enhancing lung maturityInj Betamethasone 2 doses for enhancing lung maturity

Timely delivery in a centre with a good neonatal backupTimely delivery in a centre with a good neonatal backup

Future PossibilitiesFuture Possibilities

PAPRE warfarin intensityPAPRE warfarin intensity

PRECLUDE primary preventionPRECLUDE primary prevention

More frequent use of LMWH, IVIGMore frequent use of LMWH, IVIG

What to do with the patient with APLA but no thrombotic What to do with the patient with APLA but no thrombotic manifestations ?manifestations ?

Although some of these patients are at risk, especially those Although some of these patients are at risk, especially those with SLE, many will never develop thrombosiswith SLE, many will never develop thrombosis

The current recommendation would be to do very careful The current recommendation would be to do very careful search for thrombosis. Brain MRI in patients with SLE & in search for thrombosis. Brain MRI in patients with SLE & in patients with any neurological symptompatients with any neurological symptom

If this work-up is negative follow the patient very closelyIf this work-up is negative follow the patient very closely

Does immunosuppression work ?Does immunosuppression work ?

APLA seems like an autoimmune disease, butAPLA seems like an autoimmune disease, but immunosuppression does not prevent recurrent thrombosis, immunosuppression does not prevent recurrent thrombosis, fetal loss, or neurological syndromes & so no role in the Rx fetal loss, or neurological syndromes & so no role in the Rx of thrombotic APLAof thrombotic APLA

In"catastrophic APLA" plasmapheresis may play a crucial In"catastrophic APLA" plasmapheresis may play a crucial role.role.

Low intensity anticoagulation with warfarin appears to be Low intensity anticoagulation with warfarin appears to be mostly effective in APLA (except patients with venous mostly effective in APLA (except patients with venous thrombosis) thrombosis)

Many patients will fail low intensity warfarin & need more Many patients will fail low intensity warfarin & need more aggressive anticoagulationaggressive anticoagulation. .

Heparin anticoagulation appears more effective.Heparin anticoagulation appears more effective.Arterial Thrombosis: Warfarin to an INR of 2.0 - 3.0 Arterial Thrombosis: Warfarin to an INR of 2.0 - 3.0 Venous Thrombosis: Warfarin to an INR of 3.0 - 3.5. Patients Venous Thrombosis: Warfarin to an INR of 3.0 - 3.5. Patients who "break through" warfarin should receive heparin.who "break through" warfarin should receive heparin.

Inherited ThrombophiliaInherited Thrombophilia

Inherited ThrombophiliaInherited Thrombophilia Three important inherited thrombophilias :

• Mutation in factor V Leiden causing resistance to

activated protein C (responsible of 20–30% of venous

thromboembolism events.)

• Mutation in prothrombin (guanine 20210 adenine )

• Mutation in methylene tetrahydrofolate reductase

(MTHFR) (cytosine 677 thymine (C677T) ) This

is responsible for reduced MTHFR activity & is most

frequent cause of mild hyperhomocysteinemia &

is found in 5–15% of the population.

Factor V Leiden (A506G) mutationFactor V Leiden (A506G) mutation

Present in 3-8% of the general population , Present in 3-8% of the general population , (heterozygotes) have a seven fold increased risk for (heterozygotes) have a seven fold increased risk for thrombosis whereas homozygotes have an eighty fold thrombosis whereas homozygotes have an eighty fold increase. increase.

It has been linked with an increased risk for venous It has been linked with an increased risk for venous thromboembolism due to resistance to thromboembolism due to resistance to activated activated protein C & is responsible of 20–30% of venous protein C & is responsible of 20–30% of venous thromboembolism events thromboembolism events

Protein S deficiencyProtein S deficiency

Protein S deficiency (PSD), present in up to 2% of Protein S deficiency (PSD), present in up to 2% of

general population.general population.

Found in approximately 15% of individuals with a Found in approximately 15% of individuals with a

DVT or PE .DVT or PE .

Found in 6% of women with obstetrical complications Found in 6% of women with obstetrical complications

including a relatively high risk for stillbirth. including a relatively high risk for stillbirth.

MTHFR (C677T) mutationMTHFR (C677T) mutation

A homozygous (MTHFR) mutation, present in A homozygous (MTHFR) mutation, present in

1-4% of the general population, is associated 1-4% of the general population, is associated

with a three fold increased risk for DVT or with a three fold increased risk for DVT or

PE, as well as preeclampsia & placental PE, as well as preeclampsia & placental

abruption.abruption.

MTHFR (C677T) mutationMTHFR (C677T) mutation

Responsible for reduced MTHFR activity results in Responsible for reduced MTHFR activity results in decreased synthesis of 5-methyltetrahydrofolate, the decreased synthesis of 5-methyltetrahydrofolate, the primary methyl donor in the conversion of primary methyl donor in the conversion of homocysteine to methionine & the resulting increase homocysteine to methionine & the resulting increase in plasma homocysteine concentrations in plasma homocysteine concentrations ( Hyperhomocysteinemia ) is a risk factor for ( Hyperhomocysteinemia ) is a risk factor for thrombosisthrombosis

Dietary restriction of folate & vitamin B12 remains the Dietary restriction of folate & vitamin B12 remains the most common cause. most common cause.

Prothrombin (G20210A) mutationProthrombin (G20210A) mutation

A change of G to A at position 20210 in A change of G to A at position 20210 in

prothrombin (prothrombin 20210A) elevates prothrombin (prothrombin 20210A) elevates

baseline prothrombin levels & thrombin baseline prothrombin levels & thrombin

formation. formation.

Unexplained recurrent miscarriageUnexplained recurrent miscarriage In about half the women in the research studies, no cause In about half the women in the research studies, no cause

could be found, so no specific treatment could be given.could be found, so no specific treatment could be given.

However, this group responded very well to a However, this group responded very well to a programme which removed as many stress factors as programme which removed as many stress factors as possible from their lives, resulting in an 80% success rate possible from their lives, resulting in an 80% success rate with the subsequent pregnancywith the subsequent pregnancy

Psychological support can improve outcome between Psychological support can improve outcome between the higher areas of the mind & the delicately balanced the higher areas of the mind & the delicately balanced hormonal system hormonal system

Women with unexplained recurrent miscarriage have Women with unexplained recurrent miscarriage have an excellent prognosis for future pregnancy outcome an excellent prognosis for future pregnancy outcome without pharmacological intervention if offered without pharmacological intervention if offered supportive care alone in the setting of a dedicated supportive care alone in the setting of a dedicated early pregnancy assessment unit.early pregnancy assessment unit.

After all these investigations 50% of recurrent aborters After all these investigations 50% of recurrent aborters will have no abnormalities & these should be attributed will have no abnormalities & these should be attributed to chromosomal defect in the conceptus.to chromosomal defect in the conceptus.

ConclusionConclusion In cases of adverse pregnancy outcomes APLA should be In cases of adverse pregnancy outcomes APLA should be

kept in mind kept in mind

Detailed history & tailor investigations Detailed history & tailor investigations

Couple should be counselled together . Couple should be counselled together .

The only intervention to have demonstrated benefit is serial The only intervention to have demonstrated benefit is serial ultrasound scans in early months of pregnancy.ultrasound scans in early months of pregnancy.

Referral to a tertiary unit as multidisciplinary management is Referral to a tertiary unit as multidisciplinary management is needed for patients with APLA / Thrombophillianeeded for patients with APLA / Thrombophillia

Psychological support Psychological support

Education & reassurance has an important role to playEducation & reassurance has an important role to play

Thromboprophylaxis for previous thromboembolic episode

Risk categoryp Risk factors Prophylaxis

High risk

TED (thromboembolic

disease)

-Prev. TED

-Prev TED+APLA

-Prev TED+ family history of TED

-Recurrent TED

-TED in current preg.

ANC:s/c UH or

LMWH

Intrapartum:s/c UH

or LMWH

Post partum:s/c UH

or LMWH for 3-7 days f/b UH or LMWH or warfarin for 3-7 days

Low risk One prev TED (No other risk factors)

ANC: g odd

Intrapartum or post partum:as above

Diagnosis of APLADiagnosis of APLA can be challengingcan be challenging, due to , due to fluctuating titers of the antibodies, a lack of fluctuating titers of the antibodies, a lack of agreement between laboratories concerning agreement between laboratories concerning standardization of the assays, and debates among standardization of the assays, and debates among researchers and clinicians concerning which researchers and clinicians concerning which antibodies to measure. Although multiple APLAs antibodies to measure. Although multiple APLAs might eventually be considered pathologic to might eventually be considered pathologic to pregnancies, anti-cardiolipin, anti-pregnancies, anti-cardiolipin, anti-phosphotidylserine, and the 'lupus anticoagulant' phosphotidylserine, and the 'lupus anticoagulant' are generally believed to be culprits when identified are generally believed to be culprits when identified in women with pregnancy losses.in women with pregnancy losses.

Rx APLA syndrome generally requires daily baby aspirin prior Rx APLA syndrome generally requires daily baby aspirin prior to conception & the use of baby aspirin & heparin as soon as to conception & the use of baby aspirin & heparin as soon as pregnancy is diagnosedpregnancy is diagnosed

One recently published study demonstrated an 80% success One recently published study demonstrated an 80% success rate for treatment of APLA by this approach. The 20% failure rate for treatment of APLA by this approach. The 20% failure rate is likely accounted for in large part by genetically-abnormal rate is likely accounted for in large part by genetically-abnormal losses. losses.

More aggressive treatment of APLA occasionally involves the More aggressive treatment of APLA occasionally involves the use of human intravenous immunoglobulin. This is an use of human intravenous immunoglobulin. This is an expensive therapy that has less clear-cut efficacy expensive therapy that has less clear-cut efficacy demonstrated. The use of empiric intravenous immunoglobulin demonstrated. The use of empiric intravenous immunoglobulin should generally be discouraged, and is not endorsed by the should generally be discouraged, and is not endorsed by the American College of Obstetricans and Gynecologists.American College of Obstetricans and Gynecologists.